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Abstract

Aromatase is an enzyme member of the cytochrome P450 superfamily coded by the CYP19A1 gene. Its main biological function in humans is the conversion of androgens into estrogens, transforming androstenedione into estrone and testosterone into estradiol. This enzyme is present in several tissues, and it has a key role in maintaining the androgens and estrogens level, and thereby the endocrine regulation system. Azole compounds, which are used as agrochemicals and pharmaceuticals, can be potential endocrine disruptors and thus a reason for chemical safety and human health concerns. A toxicological evaluation of commonly used azole-based drugs and agrochemicals with respect to CYP19A1 is currently requested by the European Union - Registration, Evaluation, Authorization and Restriction of Chemicals (EU-REACH) regulations to screen hazardous chemicals for chemical safety and ecotoxicology concerns. During the last decades, the reduction of in vivo tests has become indispensable in terms of resources and animal testing. Much progress has been made in understanding steroid-aromatase interactions using in silico methods, but nonsteroidal ligands such as azoles, which are widely used, have also raised potential safety concerns that remain to be explored with respect to CYP19A1 for human health. Therefore, the overall aim of this research was to explore the chemical interactions between azoles and the human aromatase CYP19A1 enzyme by using different in silico approaches, which allows to predict the biological and toxicological profile of new azoles and also provides a deeper mechanistic understanding and rationality in relation to currently available evidence with potential applications in drug discovery and risk assessment. The first part of the present work describes the development of mechanistic structural alerts of azole-based chemicals as a guide for the evaluation of activity and toxicity, and their application as classification models. The second part of this thesis uses the structure-activity relationships to explore the structural factors of azoles that affect activity/toxicity on human aromatase, which may be helpful for medicinal chemistry in the design and synthesis of new compounds against breast cancer. Finally, the thesis addresses the development of a read-across workflow and chemical categories formation to support toxicity characterization of chemicals and data gap feeling. Overall, the findings contribute to understanding the structural requirements of azole chemicals affecting the activity of human aromatase CYP19A1 using different approaches, improve the knowledge of the mechanism of action of azoles on aromatase, and explain the effect of known compounds. Other benefits to the field include streamlining the design of new azole-based drugs/chemicals according to desired medicinal/chemical applications, opening new opportunities for drug screening with anticipation of potential candidates, suggesting recommendations, and establishing future directions in terms of molecular moieties that might be associated with a particular effect under investigation.